Disease caused by Group B Neisseria meningitidis (N. meningitidis) remains a significant health problem worldwide. There are currently no effective vaccines available for this Group, although effective treatment for meningococcal infections is available with antibiotics. However, the progression of the infection can be so rapid that in some cases treatment cannot be administered in time to be effective. The threat of meningococcal disease would be most appropriately dealt with by prevention with a generally effective vaccine. There is also no vaccine to prevent infection by the related pathogen Neisseria gonorrhoea (N. gonorrhoeae). Although effective treatment of gonococcal infections is currently available with antibiotics, resistance is increasing. Furthermore, in gonococcal infections, asymptomatic carriage (particularly common in women) can result in greater susceptibility to HIV, and may also lead to pelvic inflammatory disease.
Pili of pathogenic Neisseria are typical of a family of adhesins, type IV fimbriae, found in a wide range of Gram-negative pathogens. These long polymeric proteins protrude from the bacterial surface and have a crucial role in both colonization of the host and adhesion to host cells (Virji et al., 1991; McGee & Stephens, 1984). Although there are other accessory proteins, pili are composed primarily of thousands of subunits, called pilin. Pili of pathogenic Neisseria are major virulence factors associated with adhesion, cytotoxicity, twitching motility, auto-aggregation and DNA transformation.
Typical of many surface proteins of pathogenic Neisseria, pili display both phase and antigenic variation (reviewed in Seifert, 1996) and are post-translationally modified (reviewed in Virji, 1997). Four different types of modifications have been described. A phosphodiester-linked glycerol substituent has been reported at serine 93 of the pilin molecule (Stimson et al., 1996), a phosphate group has been reported at serine 68 in N. gonorrhoeae (Forest et al., 1999), pili of both N. meningitidis and N. gonorrhoeae are glycosylated at serine 623 with a trisaccharide molecule, Gal (β1-4) Gal (α1-3) 2,4-diacetimido-2,4,6-trideoxyhexose (Stimson et al., 1995) or a disaccharide Gal (α1-3) GlcNAc (Parge et al., 1995; Marceau et al., 1998). Covalently linked phosphorylcholine (ChoP) has been reported in N. meningitidis and N. gonorrhoeae (Kolberg et al., 1997; Weiser et al., 1998) and is found on surface-exposed moieties of many different pathogens of the respiratory tract (Gillespie et al., 1996 J Med Microbiol 44:35-40). In H. influenzae, S. pneumoniae and commensal Neisseria, ChoP is attached to lipopolysaccharide (LPS) and the biosynthetic pathway is well understood (Serino and Virji, 2000 Microbiology 35:1550; Weiser et al., 1989 57:3045-52; Zhang et at, 1999 Mol Microbiol 31:1477)
However, in pathogenic Neisseria, ChoP is covalently attached to the surface exposed pili but is not found attached to the LPS (Weiser et al., 1998 Infection & Immunity 66:4263). The position of the ChoP modification has been determined in N. gonorrhoeae at Serine 68 in strain MS11 (Aas et al., 2006 Journal of Biological Chemistry. 281:27712-27723). The transferase required for the ChoP to pilin of N. meningitidis, pptA, has been identified previously (Warren and Jennings, 2003 Infection and Immunity 71:6892-68928).
The same gene was subsequently identified in N. gonorrhoeae (Hegge et al., 2004 Proc Natl Acad Sci USA 101: 10798-10803).
The role of phosphorylcholine in disease caused by pathogenic Neisseria is not known, nor has the function of pili post-translational modifications in host-pathogen interactions been resolved.